Abstract Supportive health care measures instituted during childhood successfully prevent serious infections and many other life-threatening complications of sickle cell disease (SCD), resulting in improved survival to adulthood. This has, in part, shifted the demographics of SCD to include a growing proportion of young adults with chronic health impairments. While hematopoietic cell transplantation (HCT) has curative potential, very few individuals with SCD are treated by HCT, due in part to the toxicity of this treatment. Recently, advances in Human Leukocyte Antigen (HLA) typing techniques and supportive care have improved outcomes of HCT, particularly after unrelated donor HCT. A conditioning regimen of Busulfan, Fludarabine and anti-thymocyte globulin has a reduced toxicity profile and appears effective in HCT from unrelated donors in adults who have advanced myeloid malignancies and thalassemia major. We have organized an interdisciplinary group of transplant investigators and adult sickle cell providers to test the hypothesis that HCT from an HLA-identical sibling or unrelated marrow donor is safe and effective in young adults with severe SCD. We propose to test this hypothesis in a pilot investigation, which will also serve as a central planning mechanism for designing, organizing and launching a large parallel cohort clinical trial in which transplantation and supportive treatment for adults with severe SCD will be compared. Thus, we propose to investigate HCT in adults with severe sickle cell disease by the following specific aims: 1. Determine the feasibility and tolerability of HCT in young adults with severe sickle cell disease. 2. Measure the impact of donor hematopoiesis on end-organ function and define the sample size and clinical endpoints of a larger comparative clinical trial. If successfully planned and initiated, the proposed comparative clinical trial would be the first to compare HCT and supportive care for SCD, and could broaden the therapeutic opportunities for adults with severe SCD.